The metabolic fate of a number of drugs is being further investigated in laboratory animals and in man. The purposes are to obtain more information as to differences between the species, and in particular cases the influence of disease and/or other drugs on the metabolism and the effectiveness, lack of effectiveness or aberrant toxicity in man. Phenobarbital (PB) and especially its major metabolite 4'-hydroxyphenobarbital and its conjugation products are being looked at quantitatively in the rat. Improved quantitative methods will be developed with the aid of synthesized 4'-HO-PB-15N2 and the mass spectrometric assays. Further studies of PB14C in man are planned with emphasis on quantitation of HO-PB and its conjugates. The purported anticonvulsant activity of 4'-HO-PB will be reinvestigated in mice and possibly other species (now that this compound is available by an economical synthetic method). Primidone-(Ethyl-14C) (PRM) is to be studied in man in order to ascertain whether aberrant clinical responses to this drug are related to variations in the metabolic production of its active metabolites, especially are the effects of other drugs and other factors. Concurrent further similar studies are being done in mice. Quantitation of PRM, PB and phenylethylmalonamide (PEMA, the major metabolite) is done with the aid of the 14C, solvent fractionation and TLC. With the aid of the 15N-labelled compounds and mass spectrometry we will work out better glc methodology for these three compounds together. Hexobarbital-2-14C metabolism is being studied in the dog and in man, with special emphasis on the identification and quantitation of all metabolites in urine and of the major metabolites in blood. The metabolic fate in mice of several (14C-labeled) N, N'-dialkyl barbiturates and malonamides is being studied. Tissue distributions (especially blood/brain) will be used as a basis for testing these compounds in mice for (probable) anticonvulsant activity. The purported hepatotoxicity of thiopental (p.o.) will be investigated by direct examination of rat liver microsomal enzyme protein for co-valently bound 35S.